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Mitochondrial Complex I Dysfunction in PWS

Primary Purpose

Prader-Willi Syndrome

Status
Not yet recruiting
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Coenzyme Q10
Placebo
Sponsored by
The Hospital for Sick Children
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Prader-Willi Syndrome focused on measuring CoQ10, muscle function, attention span, quality of life

Eligibility Criteria

13 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Consent provided
  2. patients with genetically confirmed PWS aged 13 to 18 years (n=14)
  3. ability to cooperate with exercise testing
  4. weight > 35.0 kg
  5. in good general health as evidenced by medical history
  6. able to take oral medications
  7. for females of reproductive potential, use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 8 weeks after the end of study intervention administration
  8. for males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner during study participation and for an additional 8 weeks after the end of study intervention administration

Exclusion Criteria:

  1. unable to perform exercise tests,
  2. already taking CoQ10
  3. having liver disease or bile duct blockage,
  4. having thyroid disease or taking thyroid medications
  5. presence of diabetes
  6. taking antiarrhythmics or antihypertensives or anti-failure medications
  7. presence of gastric disorders
  8. presence of skin disorders
  9. pregnancy or lactation
  10. lactose intolerance
  11. known allergic reaction to CoQ10 or components of preparation.
  12. treatment with another investigational drug or other intervention
  13. current smoker or tobacco use within 6 months
  14. current cannabis user or use within 6 months
  15. presence of chronic respiratory disease other than asthma
  16. presence of cardiac disease with cardiac insufficiency/CHF
  17. presence of MR-incompatible metal in body, metal devices or tattoos
  18. presence of a bleeding disorder
  19. gelatin intolerance
  20. clinically significant findings in laboratory tests at screening

Sites / Locations

  • The Hospital for Sick Children

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Coenzyme Q

Placebo

Arm Description

Each patient will be asked to take part in a 6 wk trial of pharmaceutical grade CoQ10 and will be randomly assigned to a start time. There will be a 6 wk washout period between treatment and placebo arms. At baseline, if this is the first arm, testing will include determination of muscle function based on our 3 min step test, muscle power (maximal jump, handgrip), strength (Queens' Square), endurance (6MWT), fatigue (PedsQL fatigue scale), physical activity level (3DPAR), attention (ADHDT scale), cognition (MoCA), physical function (CHAQ).and quality of life (PedQL). Following the 6 wk CoQ10 trial, testing will include repeat determination of all of the above as well as determination of total aerobic capacity (maximum cycle ergometry) and muscle metabolism (31P-MRS ergometry).

Each patient will be asked to take part in a 6 wk trial of placebo and will be randomly assigned to a start time. There will be a 6 wk washout period between treatment and placebo arms. At baseline, if this is the first arm, testing will include determination of muscle function based on our 3 min step test, muscle power (maximal jump, handgrip), strength (Queens' Square), endurance (6MWT), fatigue (PedsQL fatigue scale), physical activity level (3DPAR), attention (ADHDT scale), cognition (MoCA), physical function (CHAQ).and quality of life (PedQL). Following the 6 wk placebo trial, testing will include repeat determination of all of the above as well as determination of total aerobic capacity (maximum cycle ergometry) and muscle metabolism (31P-MRS ergometry).

Outcomes

Primary Outcome Measures

Three minute step test
Change in the baseline number of steps in 3 minutes of testing

Secondary Outcome Measures

Vertical Jump Test
Change in the baseline jumping height (centimetres)
Hand Grip Test
Change in the baseline hand grip strength (kg)
6 Minute walk test
Change in baseline number of metres walked in 6 minutes
Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale
Change in the baseline multi-dimensional fatigue scale; total score is reported. The higher the number, the greater the fatigue (range from 0 to 72).
Three Day Physical Activity Record (3DPAR)
Change in the baseline three day recall of time (number of minutes) spent at rest, and in light, moderate and vigorous activity
SWAN Rating Scale for Attention Deficit Hyperactivity Disorder (ADHD)
Change in the baseline total reported score (out of 18 items). If the sum of items 1-9 is 6 or greater, the child is likely ADHD-Inattentive type. If the sum of items 10-18 is 6 or greater, the child is likely ADHD-Hyperactive/Impulsive type. If both the sums of 1-9 and 10-18 are 6 or greater, the child is likely ADHD combined type.
Montreal Cognitive Assessment (MOCA)
Change in the baseline total cognitive score out of 30 points (range 0 to 30). The higher the number, the better the cognition.
Childhood Health Assessment Questionnaire (CHAQ)
Change in the baseline CHAQ score. Assessment of how an illness or condition affects child's ability to function in daily life. There are individual items in each of 8 sections (Arising, Eating, Dressing, Walking, Hygiene, Reach, Grip, Activities). Scoring of individual items ranges from 0-3 (0=from no difficulty to 3= unable to do). The higher the score, the more difficult is the task to a maximum of 3 points for each section. For each of the 8 sections, whatever the highest individual score was becomes the score of the section (max 3 points). Points are added to the section score if devices or aids are used for that section (to a maximum of 3 points). The CHAQ score is the total of the 8 sections, divided by 8 with a range from 0 points (no impact on quality of life) to 3 (large impact on quality of life) . The higher the score, the greater the impact of the illness on function.
Pediatric Quality of Life Index (PedQL)
Change in baseline child quality of life using pictorial scales and comparators. The lower the score, the worse the quality of life. This is scored out of 10 cm.

Full Information

First Posted
January 22, 2019
Last Updated
April 13, 2023
Sponsor
The Hospital for Sick Children
Collaborators
Foundation for Prader-Willi Research
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1. Study Identification

Unique Protocol Identification Number
NCT03831425
Brief Title
Mitochondrial Complex I Dysfunction in PWS
Official Title
Mitochondrial Complex I Dysfunction in Prader Willi Syndrome: A New Therapeutic Target
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
June 1, 2023 (Anticipated)
Primary Completion Date
June 1, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Hospital for Sick Children
Collaborators
Foundation for Prader-Willi Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Prader-Willi Syndrome (PWS) is characterized by profound infantile hypotonia, growth delay, cognitive impairment, muscle weakness and exercise intolerance. Studies have suggested that a defect in energy metabolism, yet to be clarified, may be involved in its pathogenesis. Many PWS patients have received Coenzyme Q10, but the rationale for this and objective impact on cellular metabolism has not been clarified.
Detailed Description
Investigators will determine the clinical efficacy of CoQ10 in a prospective, randomized, double-blind, controlled, cross-over study. Primary outcome will include determination of muscle function based on a 3 minute step test which showed good sensitivity in the investigators' pilot study. Secondary outcomes will determine effects on muscle power (maximal vertical jump), strength (hand grip), endurance (6 Minute Walk Test), fatigue (PedsQL quality of life scale), physical activity level (3DPAR), attention (ADHDT), cognition (MOCA), and physical function (CHAQ). The investigators' subaim is to elucidate the pathophysiologic mechanisms by which clinical improvements are mediated through interrogation of underlying mitochondrial dysfunction to optimize therapies. This will include determination of total aerobic capacity (maximal graded cycle ergometry), muscle metabolic function (31P-magnetic resonance spectroscopy (MRS) of muscle to evaluate high energy phosphagen, anaerobic and aerobic exercise metabolism), mitochondrial function (serum lactate, carnitine, acylcarnitines, lactate/pyruvate ratio), and blood and urine oxidative stress markers of lipid, protein and DNA peroxidation. Investigators hypothesize that CoQ10 will lead to a clinically significant improvement in motor function, power, fatigue, habitual activity, attention span & thereby quality of life in PWS.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prader-Willi Syndrome
Keywords
CoQ10, muscle function, attention span, quality of life

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Model Description
prospective, randomized, double-blind, controlled, cross-over study
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
The Sick Kids research pharmacist will be responsible for dispensing the CoQ10 capsules which will be of highest grade, purity and safety from Webber Natural Pharmaceuticals Limited. A placebo will be prepared by the Sick Kids research pharmacy and will consist of lactose-filled capsules. The CoQ10 and placebo capsules will not be identical in colour, shape or taste. However, as stated above, researchers, participants and families will be blinded to the treatment phase. They will know they are receiving one capsule for one part of the study and another capsule for the next part. No one (except the pharmacist and an unblinded study team member, who will only distribute and collect the medication given to the family (will not conduct any testing)) will know which capsule contains CoQ10 and which contains the placebo
Allocation
Randomized
Enrollment
14 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Coenzyme Q
Arm Type
Experimental
Arm Description
Each patient will be asked to take part in a 6 wk trial of pharmaceutical grade CoQ10 and will be randomly assigned to a start time. There will be a 6 wk washout period between treatment and placebo arms. At baseline, if this is the first arm, testing will include determination of muscle function based on our 3 min step test, muscle power (maximal jump, handgrip), strength (Queens' Square), endurance (6MWT), fatigue (PedsQL fatigue scale), physical activity level (3DPAR), attention (ADHDT scale), cognition (MoCA), physical function (CHAQ).and quality of life (PedQL). Following the 6 wk CoQ10 trial, testing will include repeat determination of all of the above as well as determination of total aerobic capacity (maximum cycle ergometry) and muscle metabolism (31P-MRS ergometry).
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Each patient will be asked to take part in a 6 wk trial of placebo and will be randomly assigned to a start time. There will be a 6 wk washout period between treatment and placebo arms. At baseline, if this is the first arm, testing will include determination of muscle function based on our 3 min step test, muscle power (maximal jump, handgrip), strength (Queens' Square), endurance (6MWT), fatigue (PedsQL fatigue scale), physical activity level (3DPAR), attention (ADHDT scale), cognition (MoCA), physical function (CHAQ).and quality of life (PedQL). Following the 6 wk placebo trial, testing will include repeat determination of all of the above as well as determination of total aerobic capacity (maximum cycle ergometry) and muscle metabolism (31P-MRS ergometry).
Intervention Type
Dietary Supplement
Intervention Name(s)
Coenzyme Q10
Intervention Description
6 week trial of either treatment with CoenzymeQ.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
6 week trial of either treatment with Placebo
Primary Outcome Measure Information:
Title
Three minute step test
Description
Change in the baseline number of steps in 3 minutes of testing
Time Frame
Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary Outcome Measure Information:
Title
Vertical Jump Test
Description
Change in the baseline jumping height (centimetres)
Time Frame
Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Title
Hand Grip Test
Description
Change in the baseline hand grip strength (kg)
Time Frame
Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Title
6 Minute walk test
Description
Change in baseline number of metres walked in 6 minutes
Time Frame
Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Title
Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale
Description
Change in the baseline multi-dimensional fatigue scale; total score is reported. The higher the number, the greater the fatigue (range from 0 to 72).
Time Frame
Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Title
Three Day Physical Activity Record (3DPAR)
Description
Change in the baseline three day recall of time (number of minutes) spent at rest, and in light, moderate and vigorous activity
Time Frame
Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Title
SWAN Rating Scale for Attention Deficit Hyperactivity Disorder (ADHD)
Description
Change in the baseline total reported score (out of 18 items). If the sum of items 1-9 is 6 or greater, the child is likely ADHD-Inattentive type. If the sum of items 10-18 is 6 or greater, the child is likely ADHD-Hyperactive/Impulsive type. If both the sums of 1-9 and 10-18 are 6 or greater, the child is likely ADHD combined type.
Time Frame
Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Title
Montreal Cognitive Assessment (MOCA)
Description
Change in the baseline total cognitive score out of 30 points (range 0 to 30). The higher the number, the better the cognition.
Time Frame
Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Title
Childhood Health Assessment Questionnaire (CHAQ)
Description
Change in the baseline CHAQ score. Assessment of how an illness or condition affects child's ability to function in daily life. There are individual items in each of 8 sections (Arising, Eating, Dressing, Walking, Hygiene, Reach, Grip, Activities). Scoring of individual items ranges from 0-3 (0=from no difficulty to 3= unable to do). The higher the score, the more difficult is the task to a maximum of 3 points for each section. For each of the 8 sections, whatever the highest individual score was becomes the score of the section (max 3 points). Points are added to the section score if devices or aids are used for that section (to a maximum of 3 points). The CHAQ score is the total of the 8 sections, divided by 8 with a range from 0 points (no impact on quality of life) to 3 (large impact on quality of life) . The higher the score, the greater the impact of the illness on function.
Time Frame
Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Title
Pediatric Quality of Life Index (PedQL)
Description
Change in baseline child quality of life using pictorial scales and comparators. The lower the score, the worse the quality of life. This is scored out of 10 cm.
Time Frame
Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Other Pre-specified Outcome Measures:
Title
Maximal Work (measured in watts ) from incremental cycle ergometry
Description
Change in the amount of work (measured in watts) in a bicycle ride to exhaustion. Participants will ride a stationary bicycle (cycle ergometer) until unable to continue. Workloads will progressively increase every minute from 'easy to pedal' to 'very hard to pedal' until participants are unable to sustain the pedalling for 1 minute. The higher the watts, the more work the participant is able to do.
Time Frame
week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Title
31-phosphorus magnetic resonance spectroscopy (MRS) ergometry
Description
Change in muscular phosphocreatine ((PCr) measured by 31P-Magnetic Resonance Spectroscopy) while performing bicycle exercise in the Magnetic Resonance scanner.
Time Frame
week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Title
Maximal Aerobic Capacity (Oxygen Uptake (VO2) in milliliters per kilogram body weight per minute)from incremental cycle ergometry
Description
Change in aerobic capacity (oxygen uptake (VO2) ml/kg/min) will be measured in a bicycle ride to exhaustion. Workloads will progressively increase every minute from 'easy to pedal' to 'very hard to pedal' until participants are unable to sustain the pedalling for 1 minute. Participants will breathe through a low resistance breathing valve and inspired and expired concentrations of oxygen and carbon dioxide will be measured to determine VO2. The higher the VO2, the higher the aerobic capacity (physical fitness).
Time Frame
week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
13 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Consent provided patients with genetically confirmed PWS aged 13 to 18 years (n=14) ability to cooperate with exercise testing weight > 35.0 kg in good general health as evidenced by medical history able to take oral medications for females of reproductive potential, use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 8 weeks after the end of study intervention administration for males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner during study participation and for an additional 8 weeks after the end of study intervention administration Exclusion Criteria: unable to perform exercise tests, already taking CoQ10 having liver disease or bile duct blockage, having thyroid disease or taking thyroid medications presence of diabetes taking antiarrhythmics or antihypertensives or anti-failure medications presence of gastric disorders presence of skin disorders pregnancy or lactation lactose intolerance known allergic reaction to CoQ10 or components of preparation. treatment with another investigational drug or other intervention current smoker or tobacco use within 6 months current cannabis user or use within 6 months presence of chronic respiratory disease other than asthma presence of cardiac disease with cardiac insufficiency/CHF presence of MR-incompatible metal in body, metal devices or tattoos presence of a bleeding disorder gelatin intolerance clinically significant findings in laboratory tests at screening
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bushra Momtaz
Phone
4168137654
Ext
224689
Email
bushra.momtaz@sickkids.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ingrid Tein, MD
Organizational Affiliation
The Hospital for Sick Children
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G1X8
Country
Canada
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ingrid Tein, MD
First Name & Middle Initial & Last Name & Degree
Greg Wells, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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Mitochondrial Complex I Dysfunction in PWS

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